LncRNA-p21 alters the antiandrogen enzalutamide-induced prostate cancer neuroendocrine differentiation via modulating the EZH2/STAT3 signaling

Autor: Yao Xiao, Liang Liang, Yuanjie Niu, Liang Cheng, Wanhai Xu, Runze Jiang, Shuyuan Yeh, Keliang Wang, Yin Sun, Jie Luo, Chawnshang Chang, Sankar N. Maity
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
General Physics and Astronomy
02 engineering and technology
Mice
SCID
Antiandrogen
urologic and male genital diseases
Neuroendocrine differentiation
Prostate cancer
chemistry.chemical_compound
Mice
STAT3
lcsh:Science
Multidisciplinary
biology
EZH2
Prostate
Cell Differentiation
021001 nanoscience & nanotechnology
3. Good health
Up-Regulation
Gene Expression Regulation
Neoplastic
Neuroendocrine Tumors
Prostatic Neoplasms
Castration-Resistant
Benzamides
Disease Progression
RNA
Long Noncoding
0210 nano-technology
Signal Transduction
STAT3 Transcription Factor
medicine.drug_class
Science
Urological cancer
macromolecular substances
General Biochemistry
Genetics and Molecular Biology
stat
Article
03 medical and health sciences
Neuroendocrine Cells
Cell Line
Tumor
Nitriles
Phenylthiohydantoin
medicine
Enzalutamide
Animals
Humans
Enhancer of Zeste Homolog 2 Protein
business.industry
Androgen Antagonists
General Chemistry
medicine.disease
Xenograft Model Antitumor Assays
Androgen receptor
030104 developmental biology
chemistry
biology.protein
Cancer research
lcsh:Q
business
Zdroj: Nature Communications, Vol 10, Iss 1, Pp 1-17 (2019)
Nature Communications
ISSN: 2041-1723
Popis: While the antiandrogen enzalutamide (Enz) extends the castration resistant prostate cancer (CRPC) patients’ survival an extra 4.8 months, it might also result in some adverse effects via inducing the neuroendocrine differentiation (NED). Here we found that lncRNA-p21 is highly expressed in the NEPC patients derived xenograft tissues (NEPC-PDX). Results from cell lines and human clinical sample surveys also revealed that lncRNA-p21 expression is up-regulated in NEPC and Enz treatment could increase the lncRNA-p21 to induce the NED. Mechanism dissection revealed that Enz could promote the lncRNA-p21 transcription via altering the androgen receptor (AR) binding to different androgen-response-elements, which switch the EZH2 function from histone-methyltransferase to non-histone methyltransferase, consequently methylating the STAT3 to promote the NED. Preclinical studies using the PDX mouse model proved that EZH2 inhibitor could block the Enz-induced NED. Together, these results suggest targeting the Enz/AR/lncRNA-p21/EZH2/STAT3 signaling may help urologists to develop a treatment for better suppression of the human CRPC progression.
The induction of neuroendocrine differentiation occurs in enzalutamide treated castration resistant prostate cancer. Here, the authors show that lncRNA-21 mediates enzalutamide induced neuroendocrine differentiation through EZH2/STAT axis and EZH2 inhibition suppresses this differentiation.
Databáze: OpenAIRE
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